Time-Dependent Bidirectional Neuroprotection by Adenosine 2A Receptor in Experimental Traumatic Brain Injury

Traumatic brain injury (TBI) results in both focal and diffuse brain pathological features that become severely exacerbated after the initial injury. Owing to this disease complexity, no effective therapeutic measure has yet been devised aimed directly at these pathological processes. We developed a clinically relevant model of TBI and tested the bidirectional neuroprotective role of adenosine 2A receptors (A2ARs) at different times.

Wistar rats were divided into 4 treatment groups (sham, TBI, A2AR agonist [CGS-21680], and A2AR antagonist [SCH-58261]) and 4 post-TBI intervals (15 minutes and 1, 12, and 24 hours). A2AR agonist and antagonist effects were tested by the neurological functional score (NFS) and levels of cyclic adenosine monophosphate, interleukin-1β, oxidative stress antioxidant markers, and caspase-3.

The A2AR agonist-treated group showed significant NFS improvement at 15 minutes and 1 hour after TBI compared with the TBI group. However, no improvement was observed at 12 and 24 hours. The A2AR antagonists resulted in no NFS improvement at 15 minutes and 1 hour, and significant improvement observed at 12 and 24 hours. Significant neuroprotective effect with an A2AR agonist were observed with cyclic adenosine monophosphate, interleukin-1β, oxidative stress markers, catalase, and caspase-3 levels at 15 minutes and 1 hour after TBI. The A2AR antagonist showed no effect at these intervals but showed a protective effect at 12 and 24 hours after TBI.

The A2AR agonist showed a beneficial neuroprotective effect at the early stages after TBI, and the A2AR antagonist showed a benefit at the later stages after TBI. These findings suggest that A2AR agonists and antagonists should be used in accordance with the point at which the TBI occurred.